Does Fibromuscular Dysplasia Cause Chronic Kidney Disease? A Two-Sample Mendelian Randomization Study

Fred Boehm (frederick.boehm@gmail.com)

Tuesday, July 16, 2024

Overview

  • Fibromuscular dysplasia (FMD) prevalence: ~ 3% (Rana and Al-Kindi 2021)
  • Women are 85% to 90% of cases (Kim et al. 2013)
  • Genome-wide association studies (GWAS) have identified variants that associate with FMD (Georges et al. 2021)
  • Two-Sample Mendelian Randomization (MR) uses GWAS results to estimate a causal effect, subject to assumptions

FMD

  • FMD affects artery walls
  • Diagnosed with angiography, but may be overlooked in clinical practice
  • Prevalence (U.S.A.): ~ 3%
  • Women are 85% to 90% of cases

Chronic Kidney Disease (CKD)

  • About one in ten people have CKD
  • Affected ~ 16% of Americans aged 20+ in 1999 to 2004
  • Causes and prevalences differ by ancestry
  • Genome-wide association studies have revealed some genetic variants that affect CKD

FMD & CKD

  • FMD is the second-most common abnormality of renal arteries (Twist, Leeuw, and Kroon 2018)
  • FMD prevalence among potential kidney donors: 2% to 6%

Mendelian Randomization: Big Picture

  • Major goal of biomedical research is to identify causes of diseases
  • Randomized controlled trials are a gold standard for causal conclusions
  • Confounding plagues observational studies that seek causal inferences
  • Germline genotypes are randomly assigned at meiosis
  • MR as “Nature’s randomized controlled trial”

Mendelian Randomization: A Method for Assessing Causal Relationships

Three Key Assumptions:

  1. SNP instruments associate with Exposure
  2. No common causes of SNPs and Outcome
  3. No Exposure-independent path between SNPs and Outcome
  • FMD is Exposure
  • CKD is Outcome

Mendelian Randomization: A Method for Assessing Causal Relationships

Causal association between mTOR-dependent EIF-4E and EIF-4A circulating protein levels and type 2 diabetes: a Mendelian randomization study - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Mendelian-Randomization-unbiased-causal-associations-and-assumptions-Mendelian_fig5_344407603 [accessed 31 Mar, 2024]

FMD & CKD: MR Inputs

  • Need GWAS Summary Statistics for FMD & CKD (with no subject overlap)
  • FMD GWAS summary statistics (Georges et al. 2021)
  • UK Biobank CKD GWAS summary statistics (women only) (Team 2018)
  • Choose a set of SNPs based on associations with FMD (p-value threshold: \(10^{-8}\))

FMD & CKD: Results

FMD & CKD: Results

Method slope se pvalue
MR Egger 0.003 0.002 0.38
Weighted Median 0.0002 0.0002 0.54
Inverse Variance Weighted - 0.0001 0.0004 0.77
Simple Mode 0.0002 0.0003 0.60
Weighted Mode 0.0002 0.0003 0.50
  • Statistical power is presumably weak here

Summary & Next Steps

  • No evidence of causal relationship between FMD and CKD (but statistical power!)
  • Further sensitivity analyses are needed to quantify effects of possible biases
  • Consider other sets of SNPs with different p-value thresholds

Acknowledgments

  • Ganesh Laboratory, including Santhi Ganesh, Kristy Hunker, Min-Lee Yang, Trisha Gupte, and Sayhaan Goraya
  • Xiang Zhou & Chang Xu
  • Cardiovascular Medicine Training Grant (NIH T32-HL007853)

Thank you!

Fred Boehm: frederick.boehm@gmail.com

https://fboehm.us/

https://github.com/fboehm/2024-cgsi-ucla/

References

Georges, Adrien, Min-Lee Yang, Takiy-Eddine Berrandou, Mark K Bakker, Ozan Dikilitas, Soto Romuald Kiando, Lijiang Ma, et al. 2021. “Genetic Investigation of Fibromuscular Dysplasia Identifies Risk Loci and Shared Genetics with Common Cardiovascular Diseases.” Nature Communications 12 (1): 6031.
Kim, Esther SH, Jeffrey W Olin, James B Froehlich, Xiaokui Gu, J Michael Bacharach, Bruce H Gray, Michael R Jaff, et al. 2013. “Clinical Manifestations of Fibromuscular Dysplasia Vary by Patient Sex: A Report of the United States Registry for Fibromuscular Dysplasia.” Journal of the American College of Cardiology 62 (21): 2026–28.
Rana, Mariam Nadeem, and Sadeer G Al-Kindi. 2021. “Prevalence and Manifestations of Diagnosed Fibromuscular Dysplasia by Sex and Race: Analysis of> 4500 FMD Cases in the United States.” Heart & Lung 50 (1): 168–73.
Team, Neale Research. 2018. “UK Biobank GWAS Results.” 2018. https://www.nealelab.is/uk-biobank.
Twist, Daan JL van, Peter W de Leeuw, and Abraham A Kroon. 2018. “Renal Artery Fibromuscular Dysplasia and Its Effect on the Kidney.” Hypertension Research 41 (9): 639–48.